Gα-Mediated Inhibition of Developmental Signal Response

Brzostowski, Joseph; Johnson, C. G.; Kimmel, Alan R.

doi:10.1016/s0960-9822(02)00953-3

Cited by 41 publications

(44 citation statements)

References 42 publications

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“…Phenotypic data from gain-and loss-of-function mutants indicate that G␣9 regulates cAMP wave propagation (Brzostowski et al 2002). To examine this, we starved wild-type cells, g␣9-null cells, or wild-type cells expressing constitutively activated G␣9 Q196L (G␣9 Q196L cells) on an agarose substratum and compared the periodicity of cAMP waves emanating from signaling centers during the early stages of aggregation.…”

Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

“…] cells express G␣9 at levels far in excess of endogenous expression (Brzostowski et al 2002), but do not exhibit a dominant phenotype.…”

Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

“…To understand this regulation, we chose to quantify the level of total (intracellular and extracellular) cAMP produced in vivo in response to an exogenous cAMP stimulus. We first synchronously entrained wild-type, g␣9-null, and G␣9 Q196L cells with an identical regimen of exogenous cAMP pulses for 6 h to normalize their rates of differentiation (Brzostowski et al 2002) so that all cells were at an equivalent developmental stage when studied. In addition, we determined that overall CAR1 affinity for cAMP is not altered by the loss of G␣9 (data not shown), indicating that the cells are similarly sensitive to cAMP stimuli.…”

Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

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A Gα-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement

Brzostowski¹,

Parent²,

Kimmel³

2004

Genes Dev.

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Chemotactic cells, including neutrophils and Dictyostelium discoideum, orient and move directionally in very shallow chemical gradients. As cells polarize, distinct structural and signaling components become spatially constrained to the leading edge or rear of the cell. It has been suggested that complex feedback loops that function downstream of receptor signaling integrate activating and inhibiting pathways to establish cell polarity within such gradients. Much effort has focused on defining activating pathways, whereas inhibitory networks have remained largely unexplored. We have identified a novel signaling function in Dictyostelium involving a G␣ subunit (G␣9) that antagonizes broad chemotactic response. Mechanistically, G␣9 functions rapidly following receptor stimulation to negatively regulate PI3K/PTEN, adenylyl cyclase, and guanylyl cyclase pathways. The coordinated activation of these pathways is required to establish the asymmetric mobilization of actin and myosin that typifies polarity and ultimately directs chemotaxis. Most dramatically, cells lacking G␣9 have extended PI(3,4,5)P 3 , cAMP, and cGMP responses and are hyperpolarized. In contrast, cells expressing constitutively activated G␣9 exhibit a reciprocal phenotype. Their second message pathways are attenuated, and they have lost the ability to suppress lateral pseudopod formation. Potentially, functionally similar G␣-mediated inhibitory signaling may exist in other eukaryotic cells to regulate chemoattractant response.[Keywords: cAMP; cGMP; PI(3,4,5)P 3 ; actin; myosin; Dictyostelium] Supplemental material is available at http://www.genesdev.org.

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Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

“…] cells express G␣9 at levels far in excess of endogenous expression (Brzostowski et al 2002), but do not exhibit a dominant phenotype.…”

Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

Section: G␣9 Negatively Regulates the Adenylyl Cyclase Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

A Gα-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement

Brzostowski¹,

Parent²,

Kimmel³

2004

Genes Dev.

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“…Dictyostelium has single genes for Gβ and Gγ, but 12 Gα genes (Wu et al, 1995;Zhang et al, 2001;Brzostowski et al, 2002). Gβ is absolutely essential for cAMP signaling, aggregation, and development.…”

Section: G Proteins Camp Affinity and Adaptationmentioning

confidence: 99%

Oscillatory signaling and network responses during the development of Dictyostelium discoideum

McMains

Liao

Kimmel

2008

Ageing Research Reviews

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Periodic biological variations reflect interactions among molecules and cells, or even organisms. The Dictyostelium cAMP oscillatory circuit is a highly robust example. cAMP oscillations in Dictyostelium arise intracellularly by a complex interplay of activating and inhibiting pathways, are transmitted extracellularly, and synchronize an entire local population. Once established, cAMP signal-relay persists stably for hours. On a two-dimensional surface, >100,000 cells may form a single coordinated territory. In suspension culture, >10 10 cells can oscillate in harmony. This review focuses on molecular mechanisms that cyclically activate and attenuate signal propagation and on chemotactic responses to oscillatory wave progression.

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“…The continuous stimulated RCK1 kinase activity might be the signal to block stimulation of some cAMP-induced pathways. RCK1 might function with or in parallel with G␣9, which was recently demonstrated to be important for regulating adaptation of some signaling pathways during aggregation (Brzostowski et al, 2002). Although individual rck1 null cells seem to chemotax more efficiently in a micropipette chemotaxis assay, the cells exhibit aggregation defects, suggesting that RCK1 plays an important part in controlling a physiological response that is more closely related to the natural biology of the organism.…”

Section: Regulation Of Rck1mentioning

confidence: 99%

A Regulator of G Protein Signaling-containing Kinase Is Important for Chemotaxis and Multicellular Development inDictyostelium

Sun

Firtel

2003

MBoC

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We have identified a gene encoding RGS domain-containing protein kinase (RCK1), a novel regulator of G protein signaling domain-containing protein kinase. RCK1 mutant strains exhibit strong aggregation and chemotaxis defects. rck1 null cells chemotax ϳ50% faster than wild-type cells, suggesting RCK1 plays a negative regulatory role in chemotaxis. Consistent with this finding, overexpression of wild-type RCK1 reduces chemotaxis speed by ϳ40%. On cAMP stimulation, RCK1 transiently translocates to the membrane/cortex region with membrane localization peaking at ϳ10 s, similar to the kinetics of membrane localization of the pleckstrin homology domain-containing proteins CRAC, Akt/PKB, and PhdA. RCK1 kinase activity also increases dramatically. The RCK1 kinase activity does not rapidly adapt, but decreases after the cAMP stimulus is removed. This is particularly novel considering that most other chemoattractant-activated kinases (e.g., Akt/PKB, ERK1, ERK2, and PAKa) rapidly adapt after activation. Using site-directed mutagenesis, we further show that both the RGS and kinase domains are required for RCK1 function and that RCK1 kinase activity is required for the delocalization of RCK1 from the plasma membrane. Genetic evidence suggests RCK1 function lies downstream from G␣2, the heterotrimeric G protein that couples to the cAMP chemoattractant receptors. We suggest that RCK1 might be part of an adaptation pathway that regulates aspects of chemotaxis in Dictyostelium.

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Gα-Mediated Inhibition of Developmental Signal Response

Abstract: We suggest that Galpha9 functions in an inhibitory-feedback pathway that regulates cAMP signaling center formation and propagation. Galpha9 may be part of the mechanism that regulates lateral signal inhibition or that modulates receptor desensitization.

Cited by 41 publications

References 42 publications

A Gα-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement

A Gα-dependent pathway that antagonizes multiple chemoattractant responses that regulate directional cell movement

Oscillatory signaling and network responses during the development of Dictyostelium discoideum

A Regulator of G Protein Signaling-containing Kinase Is Important for Chemotaxis and Multicellular Development inDictyostelium

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